Nothing Special   »   [go: up one dir, main page]

EP0616801A1 - Procédé pour la préparation à haute pression d'une dispersion de liposomes - Google Patents

Procédé pour la préparation à haute pression d'une dispersion de liposomes Download PDF

Info

Publication number
EP0616801A1
EP0616801A1 EP94810161A EP94810161A EP0616801A1 EP 0616801 A1 EP0616801 A1 EP 0616801A1 EP 94810161 A EP94810161 A EP 94810161A EP 94810161 A EP94810161 A EP 94810161A EP 0616801 A1 EP0616801 A1 EP 0616801A1
Authority
EP
European Patent Office
Prior art keywords
water
soluble
encapsulated
liposomes
substances
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP94810161A
Other languages
German (de)
English (en)
Other versions
EP0616801B1 (fr
Inventor
Lene Frederiksen
Klaus Dr. Anton
Peter Dr. Van Hoogevest
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Ciba Geigy AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba Geigy AG filed Critical Ciba Geigy AG
Publication of EP0616801A1 publication Critical patent/EP0616801A1/fr
Application granted granted Critical
Publication of EP0616801B1 publication Critical patent/EP0616801B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals

Definitions

  • the present invention relates to a new, advantageous method for producing a liposome dispersion.
  • EP European patent application
  • 178 624 a liposome dispersion with synthetic, purified sodium 1,2-di- (9-cis-octadecenoyl) -3-sn-phos - phatidyl-S-serine and 1-n-hexadecanoyl-2- (9-cis-octadecenoyl) -3-sn-phosphatidylcholine as phospholipids and lipophilic N-acetyl-D-muramyl-L-alanyl-D-isoglutaminyl-L- alanine-2- (1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy) ethylamide or hydrophilic doxorubic
  • Liposome dispersions with inclusion compounds without actual pharmacological properties such as zinc phthalocyanine, radioactive marker compounds or fluorescent compounds are also known.
  • EP-A-451 103 is mentioned, in which a liposome dispersion with zinc phthalocyanine is described, which after intravenous application can only be used in so-called photodynamic chemotherapy after stimulation with focused light (LASER).
  • the present invention has for its object to provide a new, improved process for the production of liposomes for the inclusion of water-soluble or hydrophilic substances or mixtures of substances, which in comparison with known methods the surprising advantage of increasing the proportion of substances or mixtures of substances actually included and in pharmaceutical Application offers the advantage of sterile working conditions.
  • the process according to the present invention is characterized in that a mixture consisting of at least one phospholipid b) and optionally lipophilic auxiliaries d), customary for the intended application, of a mobile carrier phase consisting of carbon dioxide and a polar organic solvent (modifier) under pressure and temperature conditions exposed to higher than the critical pressure and the critical temperature of a pure carbon dioxide phase, the available compressed mixed phase relaxed to normal pressure and into an aqueous phase containing a substance to be encapsulated in liposomes or a mixture of substances to be encapsulated with water-soluble or hydrophilic properties a) and optionally for the intended one
  • Application usual water-soluble excipients d) transferred and optionally removed the organic solvent and / or a fraction of liposomes with a desired range of the diameter separated and / or the liposomes ndispersion in a form suitable for the intended application.
  • this compressed mixed phase is mixed with an aqueous template which contains a water-soluble active ingredient such as EDATREXATE (10-EDAM). Liposomes with a high proportion of this water-soluble inclusion compound form spontaneously.
  • Liposomes have been described in numerous publications in the literature. Their structure and use have been the subject of many studies. A distinction is made between unilamellar liposomes with a double layer and multilamellar liposomes with several double layers made of phospholipids, which are arranged onion-shell-shaped. The size of the liposomes is variable between approx. 1.0 x 10- 8 to approx. 1.0 ⁇ 10 -5 m.
  • liposomes are used as carriers of other lipophilic substances with biological action such as proteins, e.g. Antibodies or enzymes, hormones, vitamins or genes, or for analytical purposes have been proposed as carriers of labeled compounds.
  • hydrophilic property of a substance or mixture of substances is understood to be the tendency, also known for surfactants, to accumulate in the phase interface of the water. This presupposes the presence of so-called hydrophilic groups in the molecular structure of the substance or mixture of substances in question, which can interact with water in the sense of an attraction.
  • a substance or mixture of substances is defined as water-soluble if a partial or complete dissolution of its sample has taken place in the aqueous phase and a subset or the total amount of the substance or mixture of substances in the solvent water is in a molecularly disperse distribution.
  • the minimum concentration of dissolved active substance in water required for effectiveness is sufficient, if appropriate in a colloidally disperse distribution, with no sedimentation of substances taking place.
  • Poorly soluble active ingredients can be converted into water-soluble, pharmaceutically acceptable salts, e.g. into a hydrobromide, hydrochloride, mesylate, acetate, succinate, lactate, tartrate, fumarate, sulfate, maleate, etc. and make them applicable for the process.
  • poorly soluble active ingredients can be rendered water-soluble by conversion into water-soluble derivatives or by adding the solubilizers (solubilizers) mentioned below.
  • Suitable pharmaceutical active ingredients are in water-soluble form, for example as water-soluble salts, anti-inflammatory agents which are present or have been made water-soluble by adding solubilizers, for example dexamethasone, sodium dexamethasone sulfate, hydrocortisone or prednisoles, coronary dilators, for example nifedipine, isosorbitol dinitrate, nitidiazole ditrate, nitrogiazole nitrate, nitrogiazole nitrate, nitrogiazole nitrate, nitrogiazole, prostaglandins, for example prostaglandin E1, E2 or F 2a 'peripheral vasodilators, for example ifenprodil, Cinepazetmaleat, cyclandelate, cinnarizine or pentoxyphylline, antibiotics, for example ampicillin, amoxycillin, cephalexin, cephradine, cefroxadine
  • propantheline, atropine or scopolamine, antitussives and antiasthmatics e.g. theophylline, aminophylline, methylephedrine, procatechol, trimethoquinol, codeine, clofedanolol or dextromethorphan, diuretics, e.g. furosemide or acetazolamide, muscle relaxants, e.g. chlorine-relaxing agents amat, tolperisone, eperisone or baclofen, weak sedatives, e.g.
  • oxazolam diazepam, clotiazepam, medazepam, temazepam or fludiazepam
  • strong sedatives e.g. sulpiride, clocapramine or zotepine, beta-blockers, e.g.
  • Antiarrhythmics eg procainamide, disopyramide, ajimalin or quinidine
  • anti-gout agents such as allopurinol
  • anticoagulants such as ticlopidine
  • antiepileptics eg phenytoin or valproate
  • antihistamines eg chlorpheniramine, clemastine, mequitazine, eg , Domperidon or Bethahistin
  • antihypertensive agents for example reserpine, rescinnamine, methyldopa, prazosin, clonidine or budralazin
  • sympathomimetics for example dihydroergotamine, isoproterenol or etilefrin, expectorants, for example bromhexine, carbocistein, L-ethyl
  • Immunosuppressants such as ciclosporin, cytostatics such as EDATREXATE (10-EDAM), doxorubicin, cytarabine, trifosamide, cyclophosphamide, fluorouracil or methotrexate, and water-soluble sulfo derivatives of phthalocyanine, e.g. Tetrasulfophthalocyanine, which can be used in photodynamic chemotherapy.
  • cytostatics such as EDATREXATE (10-EDAM)
  • doxorubicin doxorubicin
  • cytarabine trifosamide
  • cyclophosphamide cyclophosphamide
  • fluorouracil or methotrexate fluorouracil or methotrexate
  • water-soluble sulfo derivatives of phthalocyanine e.g. Tetrasulfophthalocyanine
  • the liposome dispersion can also contain other substances to be encapsulated, such as radioactive marker compounds or fluorescent compounds.
  • R 1 and R 2 with the meanings C 10-20 -acyl are preferably straight-chain C 10-20 -atkanoyl with an even number of C atoms and straight-chain C 10-20 -alkenoyl with a double bond and an even number of C atoms .
  • Straight-chain C lo - 20 alkanoyl R 1 and R 2 with an even number of C atoms are, for example, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.
  • Straight-chain C 10-20 alkenoyl R 1 and R 2 with a double bond and an even number of C atoms are, for example, 6-cis, 6-trans, 9-cis or 9-trans-dodecenoyl, -tetradecenoyl, - hexadecenoyl, octadecenoyl or icosenoyl, especially 9-cis-octadecenoyl (oleoyl).
  • a phospholipid (I) in which R 3 denotes 2-trimethylamino-1-ethyl is designated with the trivial name lecithin and a phospholipid (I) in which R 3 denotes 2-amino-1-ethyl with the trivial name cephalin.
  • Suitable are, for example, naturally occurring cephalin or lecithin, for example cephalin or lecithin from soybeans or hen's egg, with different or identical acyl groups R 1 and R 2 or mixtures thereof.
  • Synthetic, essentially pure phospholipids (I) with different or identical acyl groups R 1 and R 2 are preferred.
  • synthetic phospholipid (I) defines phospholipids which have a uniform composition with respect to R 1 and R 2 .
  • Such synthetic phospholipids are preferably the lecithins and cephalins defined above, the acyl groups R 1 and R 2 of which have a defined structure and are derived from a defined fatty acid with a degree of purity higher than approximately 95%.
  • R1 and R 2 can be the same or different and unsaturated or saturated.
  • naturally occurring phospholipids defines phospholipids which have no uniform composition with respect to R 1 and R 2 .
  • Such natural phospholipids are also lecithins and cephalins, the acyl groups R 1 and R 2 of which are structurally indefinable and derived from naturally occurring fatty acid mixtures.
  • the requirement "essentially pure" phospholipid defines a degree of purity of more than 95% (wt.) Of the phospholipid (I), which can be determined using suitable determination methods, e.g. paper chromatographically, is detectable.
  • R 1 is straight-chain C 10-20 -alkanoyl with an even number of carbon atoms and R 2 is straight-chain C 10-20 -alkenoyl with one double bond and one have an even number of carbon atoms.
  • R 1 is n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl and R 2 is 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis-hexadecenoyl, 9-cis -Octadecenoyl or 9-cis-icosenoyl.
  • R 3 is C1-4-alkyl, for example methyl or ethyl.
  • R 3 with the meanings of C 1-5 alkyl substituted by carboxy, C 2-5 alkyl substituted by hydroxy or C 2 - 5 alkyl substituted by carboxy or hydroxy, for example 2-hydroxyethyl, 2,3-dihydroxy-n- propyl, carboxymethyl, 1- or 2-carboxyethyl, dicarboxymethyl, 2-carboxy-2-hydroxyethyl or 3-carboxy-2,3-dihydroxy-n-propyi.
  • R 3 with the meaning C 2-5 alkyl substituted by carboxy and amino is, for example, 3-amino-3-carboxy-n-propyl or 2-amino-2-carboxy-n-propyl, preferably 2-amino-2-carboxyethyl .
  • Phospholipids (I) with these groups can be in salt form, for example as the sodium or potassium salt.
  • a very particularly preferred phospholipid (I) is synthetic 1-n-hexadecanoyl-2- (9-cis-octadecenoyl) -3-sn-phosphatidylcholine (POPC) with a purity of more than 95%.
  • a salt of the phospholipid (I) is preferably pharmaceutically acceptable. Salts are defined by the existence of salt-forming groups in the substituent R 3 and by the free hydroxyl group on the phosphorus. The formation of internal salts is also possible. Alkali metal salts, in particular sodium salts, are preferred.
  • Component c) - water in the purity required for the intended application - is contained in the degree of purity intended for the respective use in the liposome dispersion, which e.g. was made germ and pyrogen free according to the regulations of the national pharmacopoeia. For example, water for injections or sterilized water for injections is used.
  • the liposome dispersion may also contain further auxiliaries d) which are required, for example, for the preparation of isotonic conditions, for example ionic additives such as table salt or nonionic additives (scaffolders) such as sorbitol, mannitol or glucose or water-soluble stabilizers for the liposome dispersion such as lactose, fructose or Sucrose.
  • ionic additives such as table salt or nonionic additives (scaffolders) such as sorbitol, mannitol or glucose or water-soluble stabilizers for the liposome dispersion such as lactose, fructose or Sucrose.
  • these additives for example table salt or mannitol, are contained in the prescribed amounts which are necessary for producing isotonic conditions of the injection solutions.
  • the liposome dispersion is produced with the lipophilic auxiliary cholesterol.
  • This excipient is added to the phospholipids mentioned in the mobile carrier phase consisting of C0 2 and the modifier ethanol.
  • this mixed phase relaxes to normal pressure in the aqueous phase, liposomes are formed in which the auxiliary cholesterol is incorporated in the double layers consisting of phospholipids. Liposomes with cholesterol in the double layer are characterized by increased stability.
  • excipients which can be used for liquid pharmaceutical formulations and which increase the water-solubility of the said active ingredients, e.g. Emulsifiers, wetting agents or surfactants, in particular emulsifiers such as oleic acid, nonionic surfactants of the fatty acid polyhydroxy alcohol ester type such as sorbitan monolaurate, oleate, stearate or palmitate, sorbitan tristearate or trioleate, polyoxyethylene adducts of fatty acid polyhydroxy alcohol esters such as polyoxyethylene sorbate stearate, palmitate, tristearate or trioleate, polyethylene glycol fatty acid esters such as polyoxyethyl stearate, polyethylene glycol 400 stearate, polyethylene glycol 2000 stearate, in particular ethylene oxide propylene oxide block polymers of the type Pluronic® (Wyandotte Chem. Corp.) or Synperonic @ ( ICI).
  • Emulsifiers emulsifiers such as
  • the advantage of the method lies in its suitability that a large amount of a water-soluble substance, in particular a water-soluble pharmaceutical active substance such as EDATREXATE (10-EDAM), doxorubicin, cytarabine or trifosamide, can be encapsulated in liposomes.
  • a water-soluble pharmaceutical active substance such as EDATREXATE (10-EDAM), doxorubicin, cytarabine or trifosamide
  • the phospholipid used is preferably the natural or synthetic, essentially pure derivatives of lecithin defined above, in particular 1-n-hexadecanoyl-2- (9-cis-octadecenoyl) -3-sn-phosphatidylcholine (POPC).
  • Cholesterol is preferably used as a common lipophilic excipient.
  • the term mobile carrier phase consisting of carbon dioxide and a polar organic solvent (modifier) defines a mixed phase which consists of carbon dioxide and polar solvent under pressure and temperature conditions near or above the critical point of this mixed phase.
  • the pressure and temperature conditions to be used are higher than the critical pressure and the critical temperature of a pure carbon dioxide phase (72 bar and 32 ° C).
  • the polar organic solvent (modifier-modifier) used is preferably ethanol, but also methanol, tert-butanol, isopropanol, n-propanol, methyl isobutyl ketone, acetone etc.
  • the pressure in the mobile carrier phase consisting of carbon dioxide and the modifier, preferably ethanol, is increased in a closed apparatus, see FIG. 1, to a value of at least 72 bar.
  • Temperatures above room temperature up to approximately 100 ° C. are preferred as working temperatures, in particular at 50-60 ° C.
  • the supercritical minimum conditions for a pure CO 2 phase are approx. 72 bar and 32 ° C (slightly different information in physicochemical tables due to different measurement methods).
  • compressed mixed phase defines a homogeneous mixture under supercritical or approximately critical pressure and temperature conditions consisting of the mobile carrier phase, the phospholipid b) and, where appropriate, lipophilic auxiliaries d), in particular cholesterol, which are customary for the intended use.
  • the size of the liposomes formed in the aqueous phase depends on various framework conditions, e.g. the composition of the mobile carrier phase, the amount of the active ingredient and the lipid components, their mixing ratio and concentration in the aqueous dispersion, choice of pressure and temperature conditions, the flow rate or variation of the mixer types or capillary geometry, e.g. Length and diameter of the expansion capillary in the apparatus used for the process.
  • framework conditions e.g. the composition of the mobile carrier phase, the amount of the active ingredient and the lipid components, their mixing ratio and concentration in the aqueous dispersion, choice of pressure and temperature conditions, the flow rate or variation of the mixer types or capillary geometry, e.g. Length and diameter of the expansion capillary in the apparatus used for the process.
  • organic solvent modifier-modifier
  • Ethanol can be removed from the aqueous solution by gel filtration (Sephadex® G 50). Ethanol with CO 2 is preferably removed in the countercurrent principle using supercritical pressure and temperature conditions according to the process described in US Pat. No. 4,492,808.
  • Acidic aqueous dispersions are preferably buffered to pH 7.0 to 7.8, preferably 7.2 to 7.4.
  • pharmaceutically acceptable buffer solutions can preferably be used, the production of which in various national pharmacopoeias, e.g. the European, U.S., German or British pharmacopoeia.
  • the dispersion can also be neutralized by adding a pharmaceutically acceptable, dilute aqueous base, e.g. dilute aqueous sodium hydroxide solution. It is usually neutralized with simultaneous pH control. If necessary, fill up with sterile, germ-free and pyrogen-free water.
  • liposome dispersion e.g. by sonication with ultrasound or extrusion through straight-pored filters (e.g. Nucleopore®), a particularly uniform size distribution of the liposomes can be obtained.
  • straight-pored filters e.g. Nucleopore®
  • the separation and isolation of a fraction of large liposomes from a fraction with small liposomes is also carried out using conventional separation methods, e.g. Gel filtration or ultrafiltration, e.g. with Sepharose @ 4B or Sephacryl® (Pharmacia SE) as a carrier, or by sedimentation of the liposomes in the ultracentrifuge, e.g. with a gravitational field at 160,000 x g. For example, after several hours, e.g. centrifugation in this gravitational field for about three hours, while the small liposomes remain dispersed and can be decanted. After centrifuging several times, a complete separation of the large from the small liposomes is achieved.
  • conventional separation methods e.g. Gel filtration or ultrafiltration, e.g. with Sepharose @ 4B or Sephacryl® (Pharmacia SE) as a carrier, or by sedimentation of the liposomes in the ultracentrifuge, e.g. with a
  • Gel filtration in particular can be used to separate all the liposomes in the aqueous phase with a diameter greater than approx. 6.0 ⁇ 10 s m, as well as non-encapsulated components and excess, dispersed lipids, which are present in high molecular weight aggregates, and thus also an aqueous dispersion Prepare a fraction of liposomes of relatively uniform size.
  • liposomes and their size distribution in the aqueous phase can be demonstrated in a manner known per se using various physical measurement methods, for example with freeze-broken ones (freeze fracture) samples and thin sections in the electron microscope or by X-ray diffraction, by dynamic light scattering, by mass determination of the filtrate in the analytical ultracentrifuge and above all by spectroscopy, e.g. in the nuclear magnetic resonance spectrum ( 1 H, 13 C and 31 P).
  • the liposome dispersion can be applied directly after removal of organic solvents, but can also be converted into a lyophilisate by freeze-drying, which is reconstituted with the intended injection volume immediately before application by adding water.
  • the pumps 2 and 7 convey the CO 2 and the modifier from the storage vessels 1 and 6 into the apparatus.
  • the CO 2 pump is preferably cooled to -10 ° C., the CO 2 having a density of approx. 1 g / ml and being easy to pump.
  • the pump pressure safety device 3 shows the pressure of the pumps 2 and 7.
  • the pulse damper 4 dampens the pressure pulses of the pumps 2 and 7, which arise when the pump pistons are retracted.
  • the pump control 8 controls the flow and phase mixing ratio of the two pumps 2 and 7.
  • the sta tables mixers 9, 20, 25, 33 have no moving parts. The mixture is created by flows in a steel tube with several built-in mixing elements (flow breakers), which divides and collects the flow lines.
  • the dynamic mixer 10 has a movable part.
  • the movement creates a turbulent flow that mixes the phases used.
  • the filter 11 retains unwanted foreign particles in the mobile carrier phase consisting of C0 2 and modifier.
  • the injector 12 is provided for additional modifier additions.
  • the check valve 13 only allows the mobile carrier phase in the direction A ⁇ B. If the pressure drops in direction B and becomes smaller than in direction A, the compressed phase is refilled until stable, equal pressure conditions prevail.
  • the adjustable pressure safety valve 14 opens in the event of undesirable overpressures.
  • the cross piece 15 is open in all directions.
  • the pressure gauge 16 displays the pressure in the recycling circuit I. This is defined by the arrangement CD-19-20-FG-18-17-15-C or preferably C-15-17-18-GF-20-DC.
  • the compressed, homogeneous mixing phase is in the recycling cycle under homogeneous conditions.
  • the recycling pump 17 conveys the mobile carrier phase from CO 2 and modifier through the extraction cell 19 and the static mixer 20 in the recycling circuit I.
  • the lipophilic components (phospholipid and possibly cholesterol) in the extraction cell 19 are dissolved.
  • the UV detector 18 shows the degree of homogenization of the compressed lipid-containing mixed phase with the lipophilic components presented in the extraction cell 19. The detector signal is recorded on a recorder.
  • the extraction cell 19 represents a pressure-stable steel tube with screw connections and filters at the entrance and exit. Empty chromatographic columns can also be used for this.
  • the pressure sensor 21 measures the pressure behind the recycling circuit I.
  • the pressure regulator 22 contains a piezo crystal, which is controlled by the piezo driver 23 and thereby sets the necessary pressure conditions.
  • the Piezo Driver23 automatically sets the desired working pressure regardless of the flow conditions.
  • the amount of water-soluble or hydrophilic substance can be metered in, which is to be encapsulated in liposomes.
  • the arrangement in the relaxation area 24b-30b-31b-32b is preferred. But you can also choose the arrangement in the high pressure area 24a-30a-31a-32a.
  • the static mixer 25 serves as a homogenizer for liposome formation.
  • the recycling pump 27 conveys the aqueous phase from the collecting vessel 26 through the static mixer 33 into the recycling circuit II. This is defined by the arrangement 29-34-26-27-29.
  • the water bath 28 ensures constant temperature conditions in the recycling circuit I, in the pump head of the recycling pump 17 and in the detection cell 18.
  • the three-way taps A, C, D, F, G, I, J, L, N conduct the streams of the compressed phase ( one exit always open) or distribute it in two directions (two exits open).
  • the two-way taps B, E, H, K, M, O conduct or block the flows.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP94810161A 1993-03-24 1994-03-15 Procédé pour la préparation à haute pression d'une dispersion de liposomes Expired - Lifetime EP0616801B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH891/93 1993-03-24
CH89193 1993-03-24

Publications (2)

Publication Number Publication Date
EP0616801A1 true EP0616801A1 (fr) 1994-09-28
EP0616801B1 EP0616801B1 (fr) 1998-05-27

Family

ID=4197591

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94810161A Expired - Lifetime EP0616801B1 (fr) 1993-03-24 1994-03-15 Procédé pour la préparation à haute pression d'une dispersion de liposomes

Country Status (15)

Country Link
US (1) US5700482A (fr)
EP (1) EP0616801B1 (fr)
JP (1) JPH06315624A (fr)
KR (1) KR940021050A (fr)
AT (1) ATE166573T1 (fr)
AU (1) AU676257B2 (fr)
CA (1) CA2119610C (fr)
DE (1) DE59406065D1 (fr)
FI (1) FI111687B (fr)
HU (1) HU219352B (fr)
IL (1) IL109070A (fr)
NO (1) NO306846B1 (fr)
NZ (1) NZ260154A (fr)
PH (1) PH30470A (fr)
ZA (1) ZA942037B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0706821A1 (fr) * 1994-10-06 1996-04-17 Centre De Microencapsulation Procédé pour l'enrobage de particules
WO1996015774A1 (fr) * 1994-11-18 1996-05-30 Aphios Corporation Procedes et dispositifs de confection de liposome contenant des medicaments hydrophobes
EP0834309A2 (fr) * 1996-09-27 1998-04-08 Artur Herzog Dr. Mesmer Utilisation d'une solution de liposomes pour augmenter l'activité et/ou diminuer la toxicité de médicaments
DE19711393C1 (de) * 1997-03-19 1998-08-13 Fraunhofer Ges Forschung Verfahren zum Mikroverkapseln von Partikeln
US6375930B2 (en) 1996-06-04 2002-04-23 Board Of Regents, The University Of Texas System Membrane incorporation of texaphyrins
EP1776948A1 (fr) * 2004-08-11 2007-04-25 Konica Minolta Medical & Graphic, Inc. Technique de production des preparations contenant des liposomes
WO2019191627A1 (fr) 2018-03-30 2019-10-03 Insmed Incorporated Procédés pour la fabrication continue de produits médicamenteux liposomaux
EP3705179A4 (fr) * 2017-11-01 2020-11-11 Osaka University Développement de procédé et d'appareil de production de particules lipidiques ayant un diamètre de particule recherché

Families Citing this family (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4445341A1 (de) * 1994-12-19 1996-06-20 Basf Ag Verfahren und Vorrichtung zur Herstellung wirkstoffhaltiger Dispersionen
ATE535232T1 (de) 1997-09-18 2011-12-15 Pacira Pharmaceuticals Inc Retardierte freisetzung liposomaler anesthetischer zusammensetzungen
ES2384094T3 (es) * 1997-11-14 2012-06-29 Pacira Pharmaceuticals, Inc. Producción de liposomas multivesiculares
WO1999040771A2 (fr) * 1998-02-13 1999-08-19 Selective Genetics, Inc. Procedes de melange de flux en parallele, appareils de preparation de vecteurs pour la therapie genique et compositions preparees de cette maniere
US6706280B2 (en) * 1998-08-19 2004-03-16 Bracco Research S.A. Carboxylated phosphatidic acid esters
US6855296B1 (en) 1998-11-13 2005-02-15 Optime Therapeutics, Inc. Method and apparatus for liposome production
JP2002529240A (ja) * 1998-11-13 2002-09-10 オプタイム セラピュウティクス， インコーポレイテッド リポソーム生成のための方法および装置
FR2803539B1 (fr) * 2000-01-07 2002-07-12 Separex Sa Procede de captage et d'encapsulation de fines particules
US20040099976A1 (en) * 2000-10-13 2004-05-27 Katsuto Otake Process for producing liposome and apparatus therefor
IL156976A0 (en) * 2001-02-13 2004-02-08 Yissum Res Dev Co Carotenoid-loaded liposomes
WO2002089851A1 (fr) * 2001-03-06 2002-11-14 Separex (Societe Anonyme) Procede de fabrication de complexes hote-client
FR2830760B1 (fr) * 2001-10-12 2004-06-04 Pf Medicament Procede de preparation d'un compose d'interaction de substances actives avec un support poreux par fluide supercritique
FR2854079B1 (fr) * 2003-04-25 2007-11-30 Pf Medicament Procede de preparation de complexes moleculaires
JP4595319B2 (ja) * 2003-12-03 2010-12-08 コニカミノルタエムジー株式会社 リポソーム用脂質、リポソームおよびそれらの製造方法
SI1718283T1 (sl) 2004-01-22 2013-06-28 University Of Miami Topične formulacije koencima Q10 in postopki uporabe
JP4649841B2 (ja) * 2004-02-18 2011-03-16 コニカミノルタエムジー株式会社 リポソーム含有製剤の製造方法、およびリポソーム含有製剤
JPWO2006009022A1 (ja) * 2004-07-21 2008-05-01 コニカミノルタエムジー株式会社 リポソーム含有ｘ線造影剤およびその製造方法
JP2006056807A (ja) * 2004-08-18 2006-03-02 Konica Minolta Medical & Graphic Inc 光線力学療法製剤
JP4715133B2 (ja) * 2004-08-26 2011-07-06 コニカミノルタエムジー株式会社 抗腫瘍リポソーム製剤およびその製造方法
JP2006069929A (ja) * 2004-08-31 2006-03-16 Konica Minolta Medical & Graphic Inc 真菌症治療製剤およびその製造方法
WO2006071659A1 (fr) * 2004-12-29 2006-07-06 Trustees Of Boston University Delivrance d'antagonistes h2
EP1882055A1 (fr) * 2005-04-15 2008-01-30 Advanced Technology Materials, Inc. Appareil et procedes de suppression ou de depot de fluides supercritiques
JP2006298838A (ja) * 2005-04-21 2006-11-02 Konica Minolta Medical & Graphic Inc リポソーム含有ｘ線造影剤
FR2889665B1 (fr) * 2005-08-12 2007-11-09 Pic Solution Soc Par Actions S Procede et installation pour la regulation du taux de modificateur dans une chromatographie ou extraction supercritique avec recyclage
JP2007217369A (ja) * 2006-02-17 2007-08-30 Trendy:Kk 除毛剤、除毛剤の製造方法、および除毛方法
CA2823407C (fr) 2007-03-22 2016-10-18 Berg Pharma Llc Formulations topiques ayant une biodisponibilite amplifiee
CA2721071C (fr) 2008-04-11 2017-10-17 Cytotech Labs, Llc Procedes et utilisation d'induction de l'apoptose dans des cellules cancereuses
US9445975B2 (en) 2008-10-03 2016-09-20 Access Business Group International, Llc Composition and method for preparing stable unilamellar liposomal suspension
CA2762213A1 (fr) 2009-05-11 2010-11-18 Berg Biosystems, Llc Methodes de diagnostic de troubles metaboliques a l'aide de decaleurs epimetaboliques, de molecules intracellulaires multidimensionnelles ou d'influenceurs environnementaux
EP3366280A1 (fr) * 2010-03-12 2018-08-29 Berg LLC Préparations intraveineuses de coenzyme q10 (coq10) et leurs procédés d'utilisation
US20120269867A1 (en) 2011-04-04 2012-10-25 Jimenez Joaquin J Methods of treating central nervous system tumors
SG10201605008TA (en) 2011-06-17 2016-07-28 Berg Llc Inhalable pharmaceutical compositions
WO2013093891A1 (fr) 2011-12-22 2013-06-27 Nuvo Research Gmbh Compositions liposomales comprenant des chlorites ou chlorates
KR102279451B1 (ko) 2013-04-08 2021-07-19 버그 엘엘씨 코엔자임 q10 병용 요법을 이용한 암 치료
AU2014315186B2 (en) 2013-09-04 2020-02-27 Berg Llc Methods of treatment of cancer by continuous infusion of coenzyme Q10
JP6316182B2 (ja) * 2014-12-19 2018-04-25 富士フイルム株式会社 リポソームの製造方法及びリポソーム製造装置
US11033495B1 (en) 2021-01-22 2021-06-15 Pacira Pharmaceuticals, Inc. Manufacturing of bupivacaine multivesicular liposomes
US11278494B1 (en) 2021-01-22 2022-03-22 Pacira Pharmaceuticals, Inc. Manufacturing of bupivacaine multivesicular liposomes
US11357727B1 (en) 2021-01-22 2022-06-14 Pacira Pharmaceuticals, Inc. Manufacturing of bupivacaine multivesicular liposomes
CN114469733B (zh) * 2021-10-13 2023-06-09 成都科建生物医药有限公司 一种阿霉素脂质体的制备装置与制备方法
CN114469734B (zh) * 2021-10-13 2023-08-04 成都科建生物医药有限公司 一种蒽环类药物脂质体的制备装置与制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2550706A1 (fr) * 1983-08-17 1985-02-22 Sterwin Ag
WO1988001864A1 (fr) * 1986-09-18 1988-03-24 Liposome Technology, Inc. Procede de traitement d'un liposome a concentration elevee

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1260393A (fr) * 1984-10-16 1989-09-26 Lajos Tarcsay Liposomes de lipides synthetiques
US4752425A (en) * 1986-09-18 1988-06-21 Liposome Technology, Inc. High-encapsulation liposome processing method
DE3812816A1 (de) * 1988-04-16 1989-11-02 Lawaczeck Ruediger Dipl Phys P Verfahren zur solubilisierung von liposomen und/oder biologischer membranen sowie deren verwendung
US5123414A (en) * 1989-12-22 1992-06-23 Unger Evan C Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
US5270053A (en) * 1990-04-03 1993-12-14 Ciba-Geigy Corp. Parenterally administerable liposome formulation comprising synthetic lipid

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2550706A1 (fr) * 1983-08-17 1985-02-22 Sterwin Ag
WO1988001864A1 (fr) * 1986-09-18 1988-03-24 Liposome Technology, Inc. Procede de traitement d'un liposome a concentration elevee

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087003A (en) * 1994-10-06 2000-07-11 Centre De Microencapsulation Method of coating particles and coated spherical particles
WO1996011055A1 (fr) * 1994-10-06 1996-04-18 Centre De Microencapsulation Procede de revetement de particules
EP0706821A1 (fr) * 1994-10-06 1996-04-17 Centre De Microencapsulation Procédé pour l'enrobage de particules
WO1996015774A1 (fr) * 1994-11-18 1996-05-30 Aphios Corporation Procedes et dispositifs de confection de liposome contenant des medicaments hydrophobes
US6375930B2 (en) 1996-06-04 2002-04-23 Board Of Regents, The University Of Texas System Membrane incorporation of texaphyrins
EP0834309A2 (fr) * 1996-09-27 1998-04-08 Artur Herzog Dr. Mesmer Utilisation d'une solution de liposomes pour augmenter l'activité et/ou diminuer la toxicité de médicaments
EP0834309A3 (fr) * 1996-09-27 2000-01-19 Artur Herzog Dr. Mesmer Utilisation d'une solution de liposomes pour augmenter l'activité et/ou diminuer la toxicité de médicaments
DE19711393C1 (de) * 1997-03-19 1998-08-13 Fraunhofer Ges Forschung Verfahren zum Mikroverkapseln von Partikeln
EP1776948A1 (fr) * 2004-08-11 2007-04-25 Konica Minolta Medical & Graphic, Inc. Technique de production des preparations contenant des liposomes
EP1776948A4 (fr) * 2004-08-11 2012-06-20 Konica Minolta Med & Graphic Technique de production des preparations contenant des liposomes
US8480952B2 (en) 2004-08-11 2013-07-09 Konica Minolta Medical & Graphic, Inc. Method of manufacturing pharmaceutical preparations containing liposomes
EP3705179A4 (fr) * 2017-11-01 2020-11-11 Osaka University Développement de procédé et d'appareil de production de particules lipidiques ayant un diamètre de particule recherché
US11638695B2 (en) 2017-11-01 2023-05-02 Osaka University Development of method and apparatus for producing lipid particles having desired particle diameter
WO2019191627A1 (fr) 2018-03-30 2019-10-03 Insmed Incorporated Procédés pour la fabrication continue de produits médicamenteux liposomaux

Also Published As

Publication number Publication date
IL109070A0 (en) 1994-06-24
HUT67384A (en) 1995-04-28
NZ260154A (en) 1995-08-28
NO941054L (no) 1994-09-26
AU5788894A (en) 1994-09-29
HU219352B (en) 2001-03-28
AU676257B2 (en) 1997-03-06
KR940021050A (ko) 1994-10-17
JPH06315624A (ja) 1994-11-15
FI941317A0 (fi) 1994-03-21
DE59406065D1 (de) 1998-07-02
CA2119610A1 (fr) 1994-09-25
ZA942037B (en) 1994-09-26
EP0616801B1 (fr) 1998-05-27
IL109070A (en) 1998-04-05
PH30470A (en) 1997-05-28
NO306846B1 (no) 2000-01-03
FI111687B (fi) 2003-09-15
US5700482A (en) 1997-12-23
ATE166573T1 (de) 1998-06-15
HU9400827D0 (en) 1994-06-28
FI941317A (fi) 1994-09-25
CA2119610C (fr) 2003-07-08
NO941054D0 (no) 1994-03-23

Similar Documents

Publication Publication Date Title
EP0616801B1 (fr) Procédé pour la préparation à haute pression d'une dispersion de liposomes
DE69011922T2 (de) Arzneiemulsionen.
DE3853191T2 (de) Arzneimittelträger.
DE69535297T2 (de) Zubereitung multivesikulärer liposomen zur gesteuerten freisetzung von wirkstoffen
DE3686797T2 (de) Emulsionen zur verabreichung in wasser schwerloeslicher ionisierbarer basischer hydrophober arzneistoffe.
DE3915617B4 (de) Verwendung einer ein Cyclosporin enthaltenden Zusammensetzung zur topischen Applikation
DE69717095T2 (de) Topische vitamin d zusammensetzung auf liposomenbasis
DE69734742T2 (de) Arzneizusammensetzungen enthaltend Ascomycinderivate
DE69531179T2 (de) Nanoemulsion von dem Öl-in-Wasser Typ, gebrauchbar als ein ophthalmischen Vehikel und Verfahren zur seiner Herstellung
DE69632408T2 (de) Stabilisierte und steril filtrierbare nanopartikel
DE60118395T2 (de) Pharmazeutische zusammensetzungen mit verzögerter freisetzung für die parenterale applikation von hydrophilen wirkstoffen
DE69917609T2 (de) Arzneimittel und deren verwendung
EP0256285B1 (fr) Formulation pharmaceutique et son procédé de préparation
DE69809074T2 (de) Herstellung von arzneimitteln
DE69825137T2 (de) Liposomale Erythropoietin-Dispersion
EP0711557A1 (fr) Base pour formulations pharmaceutiques
EP0733372A2 (fr) Base pharmaceutique pour la formulation de nanosuspensions
DE3713494A1 (de) Verfahren zur herstellung einer dispersion von lipidkuegelchen in einer waessrigen phase und nach diesem verfahren erhaeltliche dispersionen
DE60018081T2 (de) Pharmazeutische zusammensetzungen zur oralen und topischen verabreichung
EP1032379B1 (fr) Composition comprenant de l'acide azelaique
DE69921409T2 (de) Cyclosporin enthaltende Zusammensetzungen
DE69130832T2 (de) Injizierbare amphotericin b enthaltende dispersion
DE19900054A1 (de) Taxane enthaltende stabile und sterile Emulsion und Verfahren zu ihrer Herstellung
EP0866689A1 (fr) Pulverisateur d'hydrocortisone pour administration topique
EP0488142B1 (fr) Procédé pour encapsuler des principes actifs lipophiles solides ou liquides dans des liposomes phospholipidiques ainsi que des médicaments contenant ces liposomes

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT SE

K1C1 Correction of patent application (title page) published

Effective date: 19940928

17P Request for examination filed

Effective date: 19950309

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: NOVARTIS AG

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

17Q First examination report despatched

Effective date: 19970423

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 19980527

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRE;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED.SCRIBED TIME-LIMIT

Effective date: 19980527

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19980527

Ref country code: ES

Free format text: THE PATENT HAS BEEN ANNULLED BY A DECISION OF A NATIONAL AUTHORITY

Effective date: 19980527

REF Corresponds to:

Ref document number: 166573

Country of ref document: AT

Date of ref document: 19980615

Kind code of ref document: T

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

GBT Gb: translation of ep patent filed (gb section 77(6)(a)/1977)

Effective date: 19980609

REF Corresponds to:

Ref document number: 59406065

Country of ref document: DE

Date of ref document: 19980702

ET Fr: translation filed
REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: GERMAN

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 19980827

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 19980827

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 19980827

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19981208

REG Reference to a national code

Ref country code: IE

Ref legal event code: FD4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19990315

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19990315

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19990331

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19990331

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19990331

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
BERE Be: lapsed

Owner name: NOVARTIS A.G.

Effective date: 19990331

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20020210

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20030218

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20030225

Year of fee payment: 10

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040315

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20041001

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20040315

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20041130

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST